XALD

X-linked adrenoleukodystrophy (X-ALD) is a rare inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene on the X chromosome. The defect impairs transport and beta-oxidation of very long-chain fatty acids (VLCFAs), leading to accumulation in the adrenal cortex, white matter of the brain, and other tissues. X-ALD is inherited in an X-linked recessive pattern; most affected individuals are males, and female carriers can have milder symptoms.

The disease presents along a spectrum. The childhood cerebral form features rapidly progressive inflammatory demyelination of brain white matter, with behavioral changes, cognitive decline, motor dysfunction, vision or hearing loss, and often adrenal insufficiency. In adulthood, the most common presentation is adrenomyeloneuropathy (AMN), a slowly progressive spinal cord demyelination causing stiffness, weakness, gait disturbance, and sometimes bladder or bowel dysfunction; adrenal insufficiency may occur at any stage.

Diagnosis relies on elevated plasma very long-chain fatty acids (VLCFAs), especially an increased C26:0 level and altered C24:0/C22:0 ratio, followed by ABCD1 gene sequencing to confirm. Brain MRI typically shows demyelination in cerebral cases, often in parieto-occipital regions. Screening for adrenal function is recommended.

Management centers on treatment of adrenal insufficiency and neurological disease. Hematopoietic stem cell transplantation (HSCT) can halt progression in selected boys with early cerebral disease. Gene therapy with elivaldogene autotemcel (Skysona) has regulatory approval for eligible pediatric patients with early cerebral X-ALD. Supportive care includes physical therapy, seizure control, and multidisciplinary support. Lorenzo’s oil has been studied but has not proven to prevent neurological decline. Prognosis depends on form and treatment timing; without treatment, cerebral X-ALD progresses to severe disability or death.